Non-vasoconstricting energy-promoting compositions containing ketone bodies

ABSTRACT

An energy-promoting composition includes a stimulant component such as caffeine, a vasodilator component, an energy source including an exogenous ketone body component, and optionally a nootropic component. The separate components beneficially and synergistically interact with one another enhances the overall energy-promoting effect of the composition more rapidly and to a greater degree than if one or more of the components are omitted. The energy-promoting composition is also formulated to minimize the crash effect common to stimulants such as energy drinks.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/864,989, filed Jun. 21, 2019, which is incorporatedherein by reference in its entirety.

BACKGROUND

Energy drinks are beverages used by consumers to promote wakefulness,maintain alertness, and enhance mood and cognition. Typical gas stationenergy drinks include common ingredients such as caffeine and sugar.Some may also include vitamins, electrolytes, or amino acids.

Despite widespread use, there are several health concerns surroundingconsumption of gas station energy drinks, particularly surrounding theireffects on the cardiovascular system. Such energy drinks have been shownto increase heart rate, increase blood pressure, and even thicken theblood. Energy drinks may also affect the brain in undesirable ways, suchas by raising stress levels and inducing anxiety, insomnia,gastrointestinal irritation, muscle twitching, and periods of prolongedrestlessness.

Energy drinks are also associated with high levels of fatigue,irritability, and sub-optimal cognition following the initial boostafter consumption. This energy “crash” can be long lasting andunpleasant. As the stimulating effects wear off, levels of adrenaline,dopamine, and acetylcholine begin to drop, and blood sugar levels mayswing erratically, often leaving the user more fatigued, irritable, andunfocused than before consuming the energy drink. In the case ofcaffeine in particular, the user's adenosine levels may continue to riseafter dosing. When caffeine is no longer available to block adenosinereceptors, the rapid flood of built up adenosine to the receptors cancontribute to the perceived crash.

To date, popular gas station energy drinks have generally failed toimprove the overall quality of life and well-being of users. Rather,such energy drinks provide a short-lived boost in desired effects butwith a subsequent crash that often tends to be so uncomfortable as tonegate the benefits and place consumption of energy drinks as a netnegative experience. When used to stay awake while driving, gas stationenergy drinks can cause high levels of stress and possibly contribute to“road rage”. For long haul drives, the energy “crash” is potentialharmful or even fatal if it leads to a highway crash.

Accordingly, there is an ongoing need for compositions that are capableof promoting a natural and sustained feeling of wakefulness, maintaininga natural feeling of alertness without jitteriness, increasingconcentration, enhancing mood, and/or enhancing cognition without thetypical energy crash and without damaging the long-term physiological ormental health of the user.

SUMMARY

Disclosed herein are energy-promoting compositions formulated to providerapid and effective onset of physical and mental energy, whileminimizing or avoiding typical crash effects that plague conventionalenergy-promoting products, particularly gas station energy drinksadvertised on billboards, radio, and television. In one embodiment, theenergy-promoting composition is formulated as a liquid energy drink.Other embodiments may include other dosage forms.

In one embodiment, the energy-promoting composition comprises: (i) astimulant component; (ii) a vasodilator component; and (iii) an energysource comprising an exogenous ketone body component. Theenergy-promoting composition may further optionally comprise (iv) anootropic component, such as a dopamine and/or acetylcholine promoter.

The stimulant component may comprise caffeine. The stimulant componentmay additionally or alternatively include other stimulant compoundsdescribed herein, such as one or more other adenosine receptorantagonists, other phosphodiesterase inhibitors, epinephrine and/ornorepinephrine promoters or combinations thereof. Caffeine is apreferred stimulant component because it is widely utilized, wellunderstood, well tolerated, easy to dose, and familiar to almost allusers.

The vasodilator component may comprise one or more of quercetin,L-citrulline and/or salt thereof, L-arginine and/or salt thereof,agmatine and/or salt thereof, nitrates, gallic acid, coenzyme Q10(CoQ10), trimethylglycine, niacin, theanine, theobromine, garlic,magnesium, grape seed extract, green tea extract, catechins and/orepicatechins (e.g., Vaso 6), cacao, proanthocyanidins, galloylatedproanthocyanidins, L-norvaline, beta-alanine, glutathione, and taurine.In some embodiments, the vasodilator component is a (−)-epicatechin suchas epicatechin-(4-8)-epicatechin-(4-8)-epicatechin orepicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate.

The energy source comprises an exogenous ketone body component, such asbeta-hydroxybutyrate and/or acetoacetate. The ketone body component maybe provided as a salt, ester, free acid (i.e., beta-hydroxybutyric acid,acetoacetic acid), or combination thereof. It may also include a ketonebody precursor, such as 1,3-butanediol or ester thereof.

The individual components of the energy-promoting compositionbeneficially and synergistically interact together to enhance theoverall energy-promoting effect of the composition and provide a morenaturally feeling energy boosting effect compared to popular gas stationenergy drinks. The combination of a stimulant component, vasodilatorcomponent, and exogenous ketone body component in a single formulationprovides benefits not obtainable from a composition that includes onlyone or two of the components.

The vasodilator component beneficially counteracts the vasoconstrictionof the stimulant component and also functions to improve thepharmacokinetic distribution of the other components. In other words,the vasodilator component functions to increase blood flow to peripheraltissues of the body so that the ketone bodies and the stimulantcompound(s) can more effectively move from the digestive system to theirintended targets (e.g., brain and muscle tissues).

The stimulant component beneficially interacts with the ketone bodycomponent by enhancing pharmacokinetic absorption and uptake of theketone bodies into the tissues so it can be readily utilized as anenergy source. In other words, the stimulant component has been found toincrease the efficiency in which the ketone body component is actuallytaken into cells and metabolized as an energy source.

The ketone body component attenuates the crash effect of the stimulantcomponent by beneficially smoothing out and/or prolonging theexperienced energy levels of the user. For example, the ketone bodycomponent provides a stable fuel source that avoids or minimizes theblood sugar swings and/or insulin spikes and/or mood swings commonlyassociated with conventional energy drinks.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

Various objects, features, characteristics and advantages of theinvention will become apparent and more readily appreciated from thefollowing description of the embodiments, taken in conjunction with theaccompanying drawings and the appended claims, all of which form a partof this specification wherein like reference numerals designatecorresponding parts in the various figures and wherein the variouselements depicted are not necessarily drawn to scale; and wherein:

FIG. 1 is a flow diagram that schematically illustrates the multipleinteractions between the individual stimulant, vasodilator, and ketonebody components of an energy-promoting composition; and

FIG. 2 is a chart that graphically illustrates the expected differencesin energy levels experienced by a typical user when consuming acomposition including caffeine (“C”), an otherwise similar compositionincluding caffeine and a vasodilator component (“C+V”), and an otherwisesimilar composition including caffeine, a vasodilator component, and aketone body component (“C+V+K”) according to the invention.

DETAILED DESCRIPTION I. Definitions

As used herein, the term “crash” or “crash effect” refers to the state auser may experience following consumption of a stimulant such ascaffeine. A crash is characterized by unpleasant effects such as extremetiredness, difficulty concentrating, irritability, diminished judgment,and/or poor mood. As the stimulant wears off, neurotransmitter and/orhormone (e.g., dopamine, acetylcholine, adrenaline) levels may droprelatively sharply, and blood sugar level swings may become larger thannormal. Insulin spikes may also exacerbate the crash. In the case ofcaffeine in particular, adenosine levels may continue to rise afterdosing. When caffeine is no longer available to block adenosinereceptors, the rapid flood of built up adenosine to the receptors cancontribute to the crash.

As used herein, the term “energy level,” “experienced energy level,” or“subjective energy level” refers to the level of wakefulness and/orfocus experienced by the user. They can be both mental and physical innature. While these may be relatively subjective properties, they arereadily understood by users and are amenable to measurement throughappropriate questioning and/or surveying. For example, as with variousclinical mood or pain rating measurements, a user may describe energylevel on a scale (e.g., 1 to 10 or 1 to 100). Other objective measuresof wakefulness are also known in the art, such as those described inMichael et al. (2008) “Effects of caffeine on alertness as measured byinfrared reflectance oculography” Psychopharmacology, 200: 255-260.

The term “administration” or “administering” is used herein to describethe process in which an energy-promoting composition is taken by ordelivered to a subject. The composition may be administered in variousways including orally, rectally, or intragastrically, among others,though typical embodiments will be formulated for oral administration.

The term “dosage form” refers to the structural form the composition isprovided in and/or the vehicle by which the autobiotic composition isdelivered to the user. Example dosage forms include, but are not limitedto, tablets, capsules, powders, gels, food products, food additives,beverages/drinks (e.g., in cans, bottles, cartons, pouches, squeezecontainers, and the like), beverage additives, candies (e.g., suckers,gummies, pastilles), food supplements, sprays, injectables, andsuppositories. Preferred embodiments are formulated as liquids for oralconsumption.

The term “unit dose” refers to a dosage form that is configured todeliver a specified quantity or dose of composition or componentthereof. Dosage forms may be configured to provide a full unit dose orfraction thereof (e.g., ½, ⅓, or ¼ of a unit dose).

Another dosage form that can be used to provide a unit dose ofcomposition or component thereof is a “unit dose measuring device”, suchas a cup, scoop, syringe, dropper, spoon, spatula, or colonic irrigationdevice, which is configured to hold therein a measured quantity ofcomposition equaling a full unit dose or fraction thereof (e.g., ½, ⅓,or ¼ of a unit dose). An example use of such measuring device(s) is inkit together with a bulk container.

For example, a “bulk container”, such as a carton, box, can, jar, bag,pouch, bottle, jug, or keg, containing several unit doses of composition(e.g., 5-250 or 10-150 unit doses) can be provided to a user togetherwith a unit dose measuring device that is configured to provide a unitdose, or fraction thereof, of composition or component thereof.

A “kit” for use in providing a composition as disclosed herein in bulkform, while providing unit doses of the composition, may comprise a bulkcontainer holding therein a quantity of composition and a unit dosemeasuring device configured to provide a unit dose, or fraction thereof,of composition or component thereof. One or more unit dose measuringdevices may be positioned inside the bulk container at the time of sale,attached to the outside of the bulk container, prepackaged with the bulkcontainer within a larger package, or provided by the seller ormanufacture for use with one or multiple bulk containers.

The kit may include instructions regarding the size of the unit dose, orfraction thereof, and the manner and frequency of administration. Theinstructions may be provided on the bulk container, prepackaged with thebulk container, placed on packaging material sold with the bulkcontainer, or otherwise provided by the seller or manufacturer (e.g., onwebsites, mailers, flyers, product literature, etc.) The instructionsfor use may include a reference on how to use the unit dose measuringdevice to properly deliver a unit dose or fraction thereof. Theinstructions may additionally or alternatively include a reference tocommon unit dose measuring devices, such as spoons, spatulas, scoops,droppers, cups, syringes, colonic irrigation device, and the like, notprovided with the bulk container (e.g., in case the provided unit dosemeasuring device is lost or misplaced). In such case, a kit may beconstructed by the end user when following instructions provided on orwith the bulk container, or otherwise provided by the seller regardingthe product and how to properly deliver a unit dose of composition, orfraction thereof.

The term “exogenous ketone body” refers to beta-hydroxybutyrate,acetoacetate, or a combination thereof. These compounds may be utilizedby a subject's body as an energy source during instances of low glucoselevels or when these compounds are supplemented in a usable form. Wherebeta-hydroxybutyrate is included, it may be provided as purified orenriched with the R enantiomer, as purified or enriched with the Senantiomer, or as a racemic mixture. The exogenous ketone bodies may beprovided in a free acid form (i.e., beta-hydroxybutyrate and/oracetoacetic acid), salt form, ester form, or combination thereof. Ketonebody precursors, such as 1,3-butanediol or ester thereof can beincluded.

II. Energy-Promoting Compositions

In one embodiment, an energy-promoting composition comprises: (i) astimulant component; (ii) a vasodilator component; and (iii) an energysource comprising an exogenous ketone body component. Theenergy-promoting composition may further optionally comprise (iv) anootropic component such as a dopamine and/or acetylcholine promoter.

A. Stimulant Component

In some embodiments, the stimulant component comprises an effectiveamount of caffeine. The caffeine may be included in an amount rangingfrom about 30 mg to about 250 mg, or about 40 mg to about 225 mg, orabout 50 mg to about 200 mg, or about 60 mg to about 180 mg, or about 80mg to about 160 mg. Caffeine is a preferred stimulant component becauseit is widely utilized, well understood, well tolerated, easy to dose,and familiar to almost all users.

Unfortunately, caffeine also causes vasoconstriction and otherassociated effects such as increased blood pressure, which areundesirable for the typical, casual user. As with other stimulants,caffeine also tends to have a crash effect where users feel tired andsluggish as the dose is metabolized and wears off.

The stimulant component may additionally or alternatively include otherstimulant compounds, such as one or more other adenosine receptorantagonists, other phosphodiesterase inhibitors, epinephrine and/ornorepinephrine promoters, or combinations thereof. Where such additionalor alternative stimulant compounds are utilized, they are preferablyprovided in an amount such that the combined stimulant compositionprovides a stimulant effect substantially similar to that provided bycaffeine in amounts within the ranges described above.

In some embodiments, the stimulant component includes other xanthinealkaloids in addition to or alternative to caffeine, such as theacrine,theobromine, theophylline, methylliberine, other caffeine analogs, orcombinations thereof. While most of these compounds are generallyeffective stimulants, most are also associated with undesirablevasoconstriction and potential increases in blood pressure, as withcaffeine. As an exception, theobromine functions as a very mildvasodilator. Theacrine and methylliberine are believed to be somewhatless vasoconstricting than caffeine, though neither are vasodilators andat best still likely have a mild vasoconstricting effect. Theacrine isoften confused with the amino acid theanine, which in contrast doespromote vasodilation. An example of methylliberine is Dynamine™manufactured by Compound Solutions, Inc.

Epinephrine and/or norepinephrine promoters, if utilized in thestimulant component, may include one or more of yohimbine, rauwolscine,Ephedra-based compounds such as ephedrine and pseudoephedrine,synephrine, octopamine, 1,3-dimethylamylamine, higenamine, clenbuterol,and adrenaline/noradrenaline reuptake inhibitors such as hordenine andatomoxetine, for example.

B. Vasodilating Component

In some embodiments, the vasodilator component comprises one or more ofquercetin, L-citrulline and salts thereof such as citrulline malate,L-arginine and salts thereof, agmatine and salts thereof, nitrates(extracts from beetroot, celery, cress, chervil, lettuce, spinach,arugula), gallic acid, coenzyme Q10 (CoQ10), trimethylglycine, niacin,theanine, theobromine, garlic, magnesium, grape seed extract, green teaextract, catechins and/or epicatechins (e.g., from green tea or and/orgrape seed), proanthocyanidins (e.g., galloylated proanthocyanids),arginase inhibitors such as L-norvaline, nitric oxide synthase promoterssuch as beta-alanine and/or glutathione, and GABA receptor agonists suchas taurine. Many of the foregoing vasodilating compounds function atleast partially as nitric oxide promoters, though others may involveother primary vasodilating mechanisms.

In general, example monomer catechins and epicatechins have thefollowing formulas and are stereoisomers of each other:

Catechins and epicatechins have vasodilating properties and can be usedin any combination or derivative, including dimers, trimers, andoligomers thereof. In some embodiments, the vasodilator componentincludes (−)-epicatechin derivatives, such asepicatechin-(4-8)-epicatechin-(4-8)-epicatechin orepicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate, the latter ofwhich is depicted below. Such compounds are described in detail in U.S.Pat. No. 6,706,756, which is incorporated herein by this reference. Anexample of epicatechin-containing supplement is Vaso 6™ manufactured byCompound Solutions, Inc.

The amount of the vasodilating component included may be variedaccording to the particular combination of compounds making up thevasodilator component. In some embodiments, the vasodilating componentis provided at a functional dose formulated to provide a vasodilatingeffect equal or substantially similar to a dose of about 1 g to about 8g citrulline, or about 2 g to about 6.5 g citrulline, or about 3 g toabout 5 g citrulline.

Several techniques are known in the art for measuring vasodilation,including those described by Lind et al. “Evaluation of four differentmethods to measure endothelium-dependent vasodilation in the humanperipheral circulation” Clin Sci (Lond), 2002 May; 102(5):561-7; Heisset al. “In vivo measurement of flow-mediated vasodilation in living ratsusing high-resolution ultrasound” Am J Physiol Heart Circ Physiol., 2008February; 294(2):H1086-93; and Yamashita et al. “The effects ofvasodilation on cardiac output measured by PiCCO” J Cardiothorac VascAnesth. 2008 October; 22(5): 688-92, for example.

C. Ketone Bodies

The energy source comprises an exogenous ketone body component such asbeta-hydroxybutyrate and/or acetoacetate. The ketone body component maybe provided as a salt, ester, free acid (i.e., beta-hydroxybutyric acid,acetoacetic acid), or combination thereof. A ketone body precursor suchas 1,3-butanediol or ester thereof may optionally be included. Exogenousketone bodies are particularly beneficial for supporting stable energylevels without excessive “jitters” and without a rapid crash followingconsumption. The brain can utilize ketone bodies as an energy source,and in many instances, ketone bodies are the preferred source of energyfor brain cells. An increase in the proportion of the brain's energydemand met by ketone bodies, as opposed to glucose, beneficiallyprovides a stable and relatively long-lasting energy source to fuel thebrain. Ketone bodies can provide an elevated fuel source without causingan insulin spike, as is common with rapid consumption of sugars.

“Beta-hydroxybutyrate,” also known as β-hydroxybutyrate,3-hydroxybutyrate, RIB, or BHB, is the deprotonated form ofbeta-hydroxybutyric acid, a hydroxycarboxylic acid having the generalformula CH₃CH₂OHCH₂COOH. The deprotonated form present at typicalbiological pH levels is CH₃CH₂OHCH₂COO⁻. The general chemical structureshown below represents beta-hydroxybutyrate compounds that may beutilized in the disclosed compositions:

where,

X can be hydrogen, metal ion, amino cation such as from an amino acid,alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is beta-hydroxybutyric acid. When Xis a metal ion or an amino cation, the compounds is abeta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, thecompounds is a beta-hydroxybutyrate ester. The foregoing compounds canbe in any desired physical form, such as crystalline, powder, solid,liquid, solution, suspension, or gel.

“Acetoacetate” is the deprotonated form of acetoacetic acid, which is aketo carboxylic acid having the formula CH₃COCH₂COOH. The deprotonatedform present at typical biological pH levels is CH₃COCH₂COO⁻. Thegeneral chemical structure shown below represents acetoacetate compoundsthat may be utilized in the disclosed compositions:

where,

X can be hydrogen, metal ion, amino cation, such as from an amino acid,alkyl, alkenyl, aryl, or acyl.

When X is a hydrogen, the compound is acetoacetic acid. When X is ametal ion or an amino cation, the compounds is an acetoacetate salt.When X is alkyl, alkenyl, aryl, or acyl, the compounds is anacetoacetate ester. The foregoing compounds can be in any desiredphysical form, such as crystalline, powder, solid, liquid, solution,suspension, or gel.

The beta-hydroxybutyrate and acetoacetate compounds described above maybe collectively referred to herein as “ketone bodies,” “exogenous ketonebodies,” a “ketone body component,” or “exogenous ketones.”

The term “beta-hydroxybutyrate mixed salt-acid composition” means acomposition that includes one or more salts of beta-hydroxybutyrate andfree beta-hydroxybutyric acid.

Similarly, the term “acetoacetate mixed salt-acid composition” means acomposition that includes one or more salts of acetoacetate and freeacetoacetic acid.

The terms “beta-hydroxybutyrate salt” and “acetoacetate salt” do notmean or imply any particular physical state, such as a crystalline,powder, other solid form, dissolved in water to form a liquid solution,dispersed in a liquid to form a suspension, or a gel. A salt can beformed in solution by neutralizing beta-hydroxybutyric acid and/oracetoacetic acid with a strong or weak base, such as an alkali oralkaline earth metal hydroxide, carbonate, or bicarbonate, basic aminoacid, and the like.

The term “free beta-hydroxybutyric acid” means the sum ofnon-deprotonated and deprotonated beta-hydroxybutyric acid molecules. Adeprotonated beta-hydroxybutyric acid molecule generally means amolecule that has released a proton to form a hydronium ion (H₃O+) and abeta-hydroxybutyrate anion (e.g., dissolved in water).

Similarly, the term “free acetoacetic acid” means the sum ofnon-deprotonated and deprotonated acetoacetic acid molecules. Adeprotonated acetoacetic acid molecule generally means a molecule thathas released a proton to form a hydronium ion (H₃O+) and an acetoacetateanion (e.g., dissolved in water).

Free beta-hydroxybutyric acid molecules are typically not deprotonatedto any significant degree when contained in a beta-hydroxybutyrate mixedsalt-acid composition in dry powder or other solid form. In such cases,the fractional amount of free beta-hydroxybutyric acid in abeta-hydroxybutyrate mixed salt-acid composition on a weight basis isthe weight of free beta-hydroxybutyric acid divided by the combinedweight of free beta-hydroxybutyric acid and beta-hydroxybutyratesalt(s). On a molar basis, the fractional amount of freebeta-hydroxybutyric acid in an beta-hydroxybutyrate mixed salt-acidcomposition are the molar equivalents of free beta-hydroxybutyric aciddivided by the sum of molar equivalents of free beta-hydroxybutyric acidand beta-hydroxybutyrate anions provided by the beta-hydroxybutyratesalt(s). Similar principles apply to acetoacetic acid.

When dissolved in water, a portion of the beta-hydroxybutyric acid willtypically dissociate into beta-hydroxybutyrate anions and hydronium ions(H₃O+). As a result, beta-hydroxybutyric acid molecules can exchangeprotons and cations with dissolved beta-hydroxybutyrate salts. Forpurposes of defining the relative amounts of beta-hydroxybutyric acidand beta-hydroxybutyrate salt(s) in a beta-hydroxybutyrate mixedsalt-acid composition, dissociation of beta-hydroxybutyric acidmolecules and the exchange of protons and cations is not understood aschanging the molar ratio of free beta-hydroxybutyric acid relative tobeta-hydroxybutyrate anions from the beta-hydroxybutyrate salt(s). Thetotal quantity of free beta-hydroxybutyric acid molecules in solution isthe sum of dissolved beta-hydroxybutyric acid molecules that are notdeprotonated and beta-hydroxybutyrate anions formed by deprotonation ofbeta-hydroxybutyric acid molecules. Similar principles apply toacetoacetic acid.

Stated another way, the total molar equivalents of beta-hydroxybutyricacid in solution, whether or not deprotonated, is understood to be thedifference between (i) the sum of molar equivalents of non-deprotonatedbeta-hydroxybutyric acid molecules and total molar equivalents ofbeta-hydroxybutyrate anions in solution (from all sources) and (ii) thetotal molar equivalents of cationic charge provided by cations from thebeta-hydroxybutyrate salt compounds (which equals the total molarequivalents of beta-hydroxybutyrate anions provided by thebeta-hydroxybutyrate salt(s)). Alkali metal cations such as sodium andpotassium provide 1 mole of cationic charge per mole of metal cations.Alkaline earth metal cations such as magnesium and calcium, on the otherhand, provide 2 moles of cationic charge per mole of metal cations. 1mole of deprotonated beta-hydroxybutyric acid molecules provide 1 moleof anionic charge and one mole of cationic charge. Similar principlesapply to acetoacetic acid.

In view of the foregoing, the molar fraction of beta-hydroxybutyric acidin solution in relation to total moles of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate mixed salt-acid composition in solution is[(i)−(ii)]÷(i), and the molar fraction of beta-hydroxybutyrate moleculesfrom the beta-hydroxybutyrate salt(s)) in solution is (ii) (i).Multiplying the molar fraction of each by 100 gives the percentage ofeach in solution. Similar principles apply to acetoacetate mixedsalt-acid compositions.

By way of example, if 100 molar equivalents of beta-hydroxybutyratemixed salt-acid composition in a dry powdered state contained 5% of freenon-deprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyratesalt(s) on a molar basis, there would be essentially 5 molar equivalentsof beta-hydroxybutyric acid molecules and 95 molar equivalents ofbeta-hydroxybutyrate anions. When there is sufficient water to dissolvethe beta-hydroxybutyrate salt(s), and if a portion of thebeta-hydroxybutyric acid molecules were deprotonated, the molarequivalents of non-deprotonated beta-hydroxybutyric acid would be lessthan 5 and the molar equivalents of beta-hydroxybutyrate anions would begreater than 95. The extent of deprotonation of beta-hydroxybutyric acidin solution is related to solution pH. Similar principles apply toacetoacetate mixed salt-acid compositions.

Beta-hydroxybutyrate mixed salt-acid compositions, when used, containone or more beta-hydroxybutyrate salts and beta-hydroxybutyric acid.Providing a quantity of beta-hydroxybutyric acid is beneficial becauseof its much quicker absorption response time compared to salt forms ofbeta-hydroxybutyrate. Moreover, even though free beta-hydroxybutyricacid is ordinarily a liquid that forms an acidic solution of low pH whenmixed in water and has an unpalatable taste, when combined with saltforms of beta-hydroxybutyrate and where the amount ofbeta-hydroxybutyric acid is relatively small relative to the saltform(s), the composition can still form a solid, powder or other formtypical of salt forms. In such case, the combined salt and acid forms ofBHB have acceptable pH and taste. beta-hydroxybutyrate mixed salt-acidcompositions have substantial advantages over pure beta-hydroxybutyratesalts, including increased absorption rate, increased bioavailability,lower electrolyte load, ease of manufacture, significantly improvedtaste, and reduced need for citric acid or other edible acids to obtaina composition with neutral or acidic pH (e.g., compositions made acidicto preserve and prevent the compositions from supporting microbialgrowth). Similar principles apply to acetoacetate mixed salt-acidcompositions.

In some embodiments, the beta-hydroxybutyrate mixed salt-acidcomposition contains less than 100% of one or more beta-hydroxybutyratesalts and greater than 0% of free beta-hydroxybutyric acid.Beta-hydroxybutyrate mixed salt-acid compositions may contain, on amolar basis, up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%,99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%,97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%,96%, or 97%, of one or more beta-hydroxybutyrate salts and at least0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%,1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, and less than 25%,20%, 15%, 10%, 8%, 6%, 5%, 4%, or 3%, of free beta-hydroxybutyric acid.The foregoing percentages are expressed on a molar basis (e.g., moles ofbeta-hydroxybutyric acid relative to total moles of beta-hydroxybutyratecompounds in both salt and acid forms). Similar principles apply toacetoacetate mixed salt-acid compositions and percentages.

The ketone body component may be included in an amount ranging fromabout 0.5 g to about 20 g, or about 1 g to about 15 g, or about 2 g toabout 10 g, or about 3 g to about 8 g. The ketone body component ispreferably comprised of a beta-hydroxybutyrate mixed acid-saltcomposition, such as a mixture of beta-hydroxybutyrate salt(s) andbeta-hydroxybutyric acid, preferably including a mixture ofbeta-hydroxybutyrate salt(s), though ketone body forms may beadditionally or alternatively included, as mentioned above, such asacetoacetate compounds.

When a salt mixture is utilized in the ketone body component, it ispreferred that the salt mixture limit the amount of sodium ions to avoidexacerbating or causing high blood pressure or other electrolyteimbalance. As explained above, the stimulant component is alreadyassociated with causing increased blood pressure. Although thevasodilator component beneficially counteracts at least some of theseeffects, excessive sodium ions in the blood may undo the benefits of thevasodilator component and/or promote other negative health effectsrelated to electrolyte imbalances and particularly sodium/potassiumimbalances. In some embodiments, the total amount of sodium provided bya daily dose of the energy-promoting composition does not exceed fourtimes the recommended daily allowance (RDA) for sodium, which in theUnited States is currently 2,400 mg for an adult. Preferably the amountof sodium is no more than three times the RDA, more preferably no morethan two times the RDA, and most preferably no more than the RDA forsodium.

In preferred embodiments, the energy-promoting composition is formulatedsuch that the molar ratio of sodium ions to potassium ions is no greaterthan about 2.5, more preferably no greater than about 2.0, or about 1.5,or even more preferably no greater than about 1.0.

An example of a supplement for providing ketone bodies is goBHB™manufactured by Compound Solutions, Inc.

D. Other Components and Aspects of Composition

In some embodiments, the energy-promoting composition omits glucose orother sugars, such as fructose, sucrose, or other simple sugars that thebody readily converts to glucose. Excess glucose can rapidly take theuser out of ketosis, where the ketone bodies are primarily used as thecellular fuel, and causes a return to glycolysis, where glucose is theprimary cellular fuel. In glycolysis, the user may be unable to reap thefull benefits of the ketone body energy source. Rather, the crash effectmay be exacerbated by the postprandial hypoglycemia (i.e., “sugarcrash”).

The energy-promoting composition may optionally include a nootropiccomponent formulated to promote cognition, mood, and/or focus, and canthereby also aid in attenuating the crash effect of the stimulantcomponent, in particular the drop in levels of dopamine and/oracetylcholine. In some embodiments, the nootropic component may includeone or more of a dopamine promoter (including dopamine precursors,dopamine receptor agonists and/or dopamine breakdown or reuptakeinhibitors), an acetylcholine promoter (including acetylcholineprecursors, acetylcholine receptor agonists, acetylcholinesteraseinhibitors, and/or acetylcholine reuptake inhibitors), and/or othernootropic compound(s).

A suitable dopamine promoter may include methylliberine, theacrine,Mucuna pruriens, tyrosine, L-DOPA (i.e., L-3,4-dihydroxyphenylalanine),phenylalanine, phenylethylamine, tolcapone, or a combination thereof. Asuitable acetylcholine promoter may include huperzine-A (toothedclubmoss extract (aerial parts) from Huperzia serrata),acetylcholinesterase inhibitor), dimethylaminoethanol, choline,alpha-glycerophosphocholine, uridine, citicoline, racetams such aspiracetam, phenylpiracetam, oxiracetam, and aniracetam, or a combinationthereof.

The nootropic component may additionally or alternatively include one ormore other nootropic compounds such as a serotonin promoter (e.g.,tryptophan, 5-hydroxytryptophan (5-HTP)), beta-alanine, D-serine,phosphatidylserine, Panax ginseng, Ginkgo biloba, Rhodiola rosea,Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvuluspluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri,Epimedium herbs, Ashwagandha herbs, a cyclic adenosine monophosphate(cAMP) modulator such as forskolin or vinpocetine, or a combinationthereof.

The energy-promoting composition may optionally include a medium chainfatty acid, salt, or ester thereof in as a supplementary source ofendogenous ketone bodies in addition to beta-hydroxybutyratesupplementation. Medium chain fatty acids, salts, or mono-, di-, ortriglycerides thereof, can be converted by the body into endogenousketone bodies. Medium chain fatty acids have from 6 to 12 carbons,preferably from 8 to 10 carbons (e.g., caproic acid, caprylic acid,capric acid, and lauric acid).

Though possibly adversely affecting taste, the energy-promotingcomposition may optionally include a short chain fatty acid, salt orester thereof, or a mono-, di- or triglyceride of the at least one shortchain fatty acid. Short chain fatty acids have less than 6 carbons(e.g., acetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, and isovaleric acid). An example short chain triglycerideis tributyrin. Such molecules can provide protection to the gut andimprove microbiome health.

The energy-promoting compositions may include flavorings that enhancethe taste. Examples include sweeteners (e.g., stevia extract, such asRebaudioside A), fruit flavors, mint flavors, other natural flavors, andthe like.

Other optional additives include thickeners (e.g., xanthan gum),emulsifiers, preservatives, flow agents (e.g., silicon dioxide), beetroot powder, beta carotene, vitamins (e.g., A, C, D, E, niacin, B6,folate, B12), minerals (e.g., iodine, magnesium, zinc, copper,manganese, chromium, fruit extracts, vegetable extracts, enzymes (e.g.,amylase, cellulase, lactase, lipase, protease), legume extracts, and thelike.

III. Actions and Effects of the Energy-Promoting Compositions

FIG. 1 is a flow chart that illustrates the interactive beneficialeffects between the major components of the energy-promotingcomposition. The combination of a stimulant component, vasodilatorcomponent, and exogenous ketone body component in a single formulationprovides benefits not obtainable from a composition that include onlyone or two of the components.

As shown, the vasodilator component beneficially functions to improvethe pharmacokinetic distribution of both the ketone body component andthe stimulant component. In other words, the vasodilator component mayfunction to increase blood flow to peripheral tissues of the body sothat the ketone bodies and the stimulant compound(s) can moreeffectively move from the digestive system to their intended targets(e.g., brain and muscle tissues).

The vasodilator component also functions to counteract the vasodilatingeffects of the stimulant component. Most stimulants, including caffeine,cause vasoconstriction and associated increases in blood pressure. Thiscan be harmful to the cardiac and vascular system. Moreover,vasoconstriction reduces blood flow and thereby lowers the efficiency ofpharmacokinetic delivery of the energy-promoting composition to theperipheral tissues of the body. The vasodilator component beneficiallycounteracts the negative vasoconstricting effects to the vascular andcardiac systems, and likewise functions to maintain effective blood flowfor more efficient delivery of the energy-promoting composition to theperipheral tissues of the body.

The stimulant component also beneficially interacts with the ketone bodycomponent by enhancing pharmacokinetic absorption and uptake of theketone bodies into the tissues so it can be readily utilized as anenergy source. In other words, the stimulant component has been found toincrease the efficiency in which the ketone body component is actuallytaken into cells and metabolized as an energy source.

The ketone body component also affects the stimulant component byattenuating the crash effect of the stimulant component. Inclusion ofthe ketone body component has been found to beneficially smooth outand/or prolong the experienced energy levels of the user. For example,as compared to a similar composition that omits ketone bodies or thatreplaces them with a sugar ingredient such as fructose, glucose, orsucrose, users report experiencing more sustained and smooth energylevels after consuming an energy-promoting composition containing theketone body component.

FIG. 1 therefore illustrates the interconnected and interactive natureof the individual components of the energy-promoting composition whencombined. Each individual component enhances the beneficial effectsand/or reduces the negative effects of one or both of the othercomponents such that the combination as a whole beneficially provides agreater effect than each component individually or even two of thecomponents combined.

FIG. 2 is a chart that illustrates the expected and observed differencesin energy levels experienced by a typical user when consuming acomposition including caffeine (“C”), an otherwise similar compositionincluding caffeine and a vasodilator component (“C+V”), and an otherwisesimilar composition including caffeine, a vasodilator component, and aketone body component (“C+V+K”) according to the invention.

As shown, the C+V composition produces a higher and faster energy peakas compared to the C composition by itself, which is due to the enhancedblood flow and enhanced delivery of caffeine to peripheral tissues.However, the C+V composition may induce a more pronounced energy crashthan the C composition by itself for the same reasons it provides a morepronounced onset of effects.

In contrast, the C+V+K composition provides energy levels thatsubstantially track the C+V composition initially. However, where theenergy provided by the C+V composition begins to drop sharply, the C+V+Kcomposition maintains a more sustained energy level due to the crashattenuating and energy sustaining properties of the ketone bodycomponent. The overall result is that the C+V+K composition provides thebenefits of rapid onset and high peak in energy, coupled with higheroverall energy levels over time, which minimize the crash effectrelative to the C and C+V compositions.

IV. Delivery Methods and Dosage Forms

The energy-promoting composition may be consumed or administered throughany acceptable administration route. In preferred embodiments, thecomposition is formulated for oral consumption as a liquid “energydrink” or “energy shot.” The liquid formulation may include othersuitable ingredients such as flavoring agents, water, carbonated water,pH modifiers (e.g., phosphoric acid, citric acid, malic acid, tartaricacid, or succinic acid), preservatives (e.g., benzoate and/or sorbatesalts), and sweeteners (e.g., sucralose, stevia saccharin, aspartame).In other embodiments the composition may be formulated as a capsule,tablet (e.g., dissolvable tablet), lozenge, powder, candy (e.g., gummy,sucker, pastille), gel, paste, mouth spray, or other dosage formsuitable for oral administration. A composition having an acidic pH(e.g., between 4-5) may be desirable as a preservative and/or to providea desirable tart or sour taste. When a beta-hydroxybutyrate mixedsalt-acid and/or acetoacetate mixed salt-acid is/are used, it may bepossible to manufacture a composition having a desired acidic pH that anadditional pH modifier (e.g., acid) may be reduced or eliminated.

When formulated as a liquid, the energy-promoting composition may beprovided in a can, bottle, flask, or other such container configured tohold a desired number of unit doses of the composition. A container mayhold, for example, about 2 ounces to about 40 ounces of theenergy-promoting composition, more typically about 2.5 ounces to 24ounces or about 3 ounces to about 12 ounces. The separate components ofthe energy-promoting composition may be diluted or concentratedaccordingly so as to provide desired levels of each component in eachcorresponding unit dose of the container. For example, a smaller “shot”may be more concentrated than a larger and more dilute drink.

A method of delivering an energy-promoting composition to a user mayinclude the steps of: 1) providing an energy-promoting compositioncomprising a stimulant component, a vasodilator component, and an energysource including a ketone body component; and 2) administering theenergy-promoting composition to the user to thereby support an energylevel of the user.

An energy-promoting composition may be taken as needed to promote higherenergy levels, to reduce fatigue, to enhance focus, and/or to improvemood. In some implementations it may be taken daily or in multiple doses(e.g., 2, 3, 4 or more) spread throughout the day.

V. Examples

The following is a description of exemplary energy-promotingcompositions useful for promoting higher energy levels, reducingfatigue, enhancing focus, and/or to improving mood.

Example 1

Sodium beta-hydroxybutyrate 1 g Potassium beta-hydroxybutyrate 1 gMagnesium beta-hydroxybutyrate 1 g Calcium beta-hydroxybutyrate 1 gCaffeine 120 mg Epicatechins 500 mg Huperzine-A 200 mcg Citric acid (pHmodifier) to yield pH of 5.5 Flavorings to taste Water 120 ml

The energy-promoting composition is a drink.

Example 2

Sodium beta-hydroxybutyrate mixed salt-acid 1 g Potassiumbeta-hydroxybutyrate mixed salt-acid 1 g Magnesium beta-hydroxybutyratemixed salt-acid 1 g Calcium beta-hydroxybutyrate mixed salt-acid 1 gCaffeine 120 mg Epicatechins 500 mg Huperzine-A 200 mcg Flavorings totaste pH 5.5 Water 120 ml

The energy-promoting composition is a drink.

Example 3

Sodium beta-hydroxybutyrate mixed salt-acid 0.35 g Potassiumbeta-hydroxybutyrate mixed salt-acid 2.65 g Magnesiumbeta-hydroxybutyrate mixed salt-acid 0-2.5 g Calciumbeta-hydroxybutyrate mixed salt-acid 0-2.5 g Caffeine 150 mgMethylliberine (Dynamine ™) 26 mg Epicatechins (Vaso 6 ™) 50 mgHuperzine-A 750 mcg Citric acid (pH modifier) Malic Acid (pH modifier)Phosphoric Acid (pH modifier) pH 5.5 Flavorings Sucralose PotassiumSorbate Sodium Benzoate Acesulfame Potassium Water to make 90 mL

The energy-promoting composition is a drink.

Example 4

Any of the foregoing examples is modified to make a powder that can beadded to water or other liquid to form a drink.

The claimed invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the claimed invention is, therefore,indicated by the appended claims rather than by the foregoingdescription. All changes that come within the meaning and range ofequivalency of the claims are to be embraced within their scope.

The invention claimed is:
 1. An energy-promoting composition,comprising: a stimulant component that interacts with at least onereceptor to increase alertness; a vasodilator component; and an energysource that is metabolized in cells to provide energy comprising anexogenous ketone body component, wherein the exogenous ketone bodycomponent comprises a mixed salt-acid including beta-hydroxybutyric acidand sodium ions and potassium ions, wherein the molar ratio of sodiumions to potassium ions is no greater than about 2.5.
 2. Theenergy-promoting composition of claim 1, wherein the stimulant componentcomprises caffeine in an amount ranging from about 30 mg to about 250mg.
 3. The energy-promoting composition of claim 1, wherein thestimulant component comprises one or more adenosine receptorantagonists, phosphodiesterase inhibitors, epinephrine and/ornorepinephrine promoters, or combinations thereof.
 4. Theenergy-promoting composition of claim 1, wherein the stimulant componentcomprises one or more xanthan alkaloids, wherein the one or more xanthanalkaloids comprises caffeine, theacrine, theobromine, theophylline,methylliberine, caffeine analogs, or combinations thereof.
 5. Theenergy-promoting composition of claim 1, wherein the vasodilatorcomponent comprises one or more of a nitric oxide promoter, an arginaseinhibitor, and a nitric oxide synthase promoter.
 6. The energy-promotingcomposition of claim 1, wherein the vasodilator component comprises oneor more of quercetin, L-citrulline and/or salt thereof, L-arginineand/or salt thereof, agmatine and/or salt thereof, nitrates, gallicacid, coenzyme Q10 (CoQ10), trimethylglycine, niacin, theanine,theobromine, garlic, magnesium, grape seed extract, green tea extract,catechins and/or epicatechins, cacao, proanthocyanidins, galloylatedproanthocyanidins, L-norvaline, beta-alanine, glutathione, and taurine.7. The energy-promoting composition of claim 6, wherein the vasodilatorcomponent comprises epicatechin-(4-8)-epicatechin-(4-8)-epicatechin orepicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate.
 8. Theenergy-promoting composition of claim 1, wherein the vasodilatorcomponent is included at a dose formulated to provide a vasodilatingeffect equal or substantially similar to a dose of about 1 g to about 8g citrulline.
 9. The energy-promoting composition of claim 1, whereinthe exogenous ketone body component comprises beta-hydroxybutyrateand/or acetoacetate each provided as a salt, ester, free acid, orcombination thereof.
 10. The energy-promoting composition of claim 1,wherein the exogenous ketone body component is included in an amountranging from about 0.5 g to about 20 g.
 11. The energy-promotingcomposition of claim 1, wherein the exogenous ketone body componentcomprises acetoacetic acid.
 12. The energy-promoting composition ofclaim 1, wherein the molar ratio of sodium ions to potassium ions is nogreater than about 1.5.
 13. The energy-promoting composition of claim 1,wherein the composition omits glucose, fructose, and sucrose.
 14. Theenergy-promoting composition of claim 1, further comprising a nootropiccomponent.
 15. The energy-promoting composition of claim 14, wherein thenootropic component comprises one or both of a dopamine promoter and anacetylcholine promoter.
 16. The energy-promoting composition of claim14, wherein the nootropic component comprises one or more ofmethylliberine, theacrine, Mucuna pruriens, tyrosine, L-DOPA (i.e.,L-3,4-dihydroxyphenylalanine), huperzine-A, dimethylaminoethanol,phenylalanine, phenylethylamine, choline, alpha-glycerophosphocholine,uridine, citicoline, a racetam, or a combination thereof.
 17. Theenergy-promoting composition of claim 14, wherein the nootropiccomponent comprises one or more of tryptophan, 5-hydroxytryptophan(5-HTP), D-serine, phosphatidylserine, Panax ginseng, Ginkgo biloba,Rhodiola rosea, Polygala tenuifolia, Muira puama, Huperzia serrata,Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica,Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs, Ashwagandhaherbs, forskolin, vinpocetine, or a combination thereof.
 18. Theenergy-promoting composition of claim 1, wherein the composition isformulated as a consumable liquid.
 19. An energy-promoting composition,comprising: a stimulant component; a vasodilator component comprising atleast one of epicatechin-(4-8)-epicatechin-(4-8)-epicatechin orepicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate; and an energysource comprising an exogenous ketone body component.
 20. Anenergy-promoting composition, comprising: a stimulant component selectedfrom the group consisting of methylliberine, adenosine receptorantagonists, phosphodiesterase inhibitors, epinephrine and/ornorepinephrine promoters, and xanthan alkaloids; a vasodilatorcomponent; a nootropic component separate from the stimulant component;and an energy source that is metabolized in cells to provide energycomprising at least one exogenous ketone body component, wherein theexogenous ketone body component comprises a mixed salt-acid includingbeta-hydroxybutyric acid and sodium ions and potassium ions, wherein themolar ratio of sodium ions to potassium ions is no greater than about2.5.
 21. An energy-promoting composition, comprising: a stimulantcomponent selected from the group consisting of caffeine, theacrine,theobromine, theophylline, methylliberine; a vasodilator component; anootropic component selected from the group consisting of Mucunapruriens, tyrosine, L-DOPA (i.e., L-3,4-dihydroxyphenylalanine),huperzine-A, dimethylaminoethanol, phenylalanine, phenylethylamine,choline, alpha-glycerophosphocholine, uridine, citicoline, tryptophan,5-hydroxytryptophan (5-HTP), D-serine, phosphatidylserine, Panaxginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muirapuama, Huperzia serrata, Eschscholzia californica, Convolvuluspluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri,Epimedium herbs, Ashwagandha herbs, forskolin, vinpocetine, andcombinations; and one or more exogenous ketone body componentscomprising a mixed salt-acid, the mixed salt-acid includingbeta-hydroxybutyric acid and sodium ions and potassium ions, wherein themolar ratio of sodium ions to potassium ions is no greater than about2.5.